Studies have focused on the interaction between human cervical epithelial cells and specific cytokines. Cervical cells secrete a multitude of cytokines that modulate inflammation and specific immunity. Studies were undertaken to determine whether (1) specific cytokines directly influenced growth and differentiation of cultured cervical epithelial cells and (2) cervical cells responded differently to cytokines at progressive stages of malignant transformation. A number of cytokines were screened for their ability to modulate proliferation of either normal, human papillomavirus (HPV)-immortalized, or malignantly transformed cervical epithelial cells. The proinflammatory cytokines interleukin-1 alpha (IL-1alpha), interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and tumor necrosis factor beta (TNFbeta) exerted differential effects on proliferation of normal versus premalignant cells. These cytokines inhibited growth of normal cells but significantly stimulated cell proliferation in 12 of 18 different HPV- immortalized and cervical carcinoma-derived cell lines. Stimulation of proliferation was dose dependent, occurred over a wide range of cytokine concentrations (10 pm to 10 nm), and was blocked by a 20-fold excess of specific inhibitors, including the IL-1 receptor antagonist or the TNF types 1 and 2 soluble receptors. Stimulation was accompanied by increased expression of RNA for amphiregulin (sevenfold), a ligand for the epidermal growth factor (EGF) receptor. Recombinant human amphiregulin was as effective as IL-1alpha or TNFalpha in promoting growth. Antibodies that blocked EGF receptor signal transduction or that neutralized amphiregulin activity blocked IL-1, and TNF stimulated proliferation. Thus, IL-1 and TNF stimulate division of immortal and malignant cervical epithelial cells through an EGF receptor-dependent autocrine pathway involving amphiregulin. These studies identify amphiregulin as an important mediator of growth in cervical epithelial cells and provide a potential mechanism for selective amplification of abnormal cells by proinflammatory cytokines.